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Hepatocellular carcinoma
CORRESPONDENCE
We strongly agree with The Lancet that had high-dose chemotherapy for breast cancer been available only in a clinical trial, this debate would not have ensued. ASCO supports full participation in clinical trials and hopes that the results of these five trials will spur additional large-scale studies, and that women will be encouraged to take part. John R Durant American Society of Clinical Oncology, Alexandria, VA 22314, USA
1 Editorial. Chaos surrounds high-dose chemotherapy for breast cancer. Lancer 1999; 353: 1633. 2 Marshall E. Embargos: good, bad, or “necessary evil”? Science 1998; 282: 860-68.
Hepatocellular carcinoma Sir-In their seminar on hepatocellular carcinoma (HCC), Daniel Schafer and Michael Sorrell (April 10, p 1253)’ mention that use of oral contraceptives is associated with HCC. They do not provide any citation or other evidence for this attribution, although they state that “the absolute risk of developing HCC [is] very small”. Oral contraceptives are used to prevent pregnancy, a physiological condition that does have, depending on the socioeconomic status of the population and other variables, a significant mortality. It would be important, particularly in this era of evidence-based medicine, to know what the absolute risk of developing HCC is compared with the mortality associated with pregnancy, before promulgating it as a condition associated with HCC. Bertrand M Bell Family Medicine, Jacobi Medical Center, Albert Einstein College of Medicine of Yeshiva University, Jack and Pearl Resnick Campus, Bronx, NY 10461, USA
1 Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999; 353: 1253-57.
Authors’ reply Sir-We
thank Bertrand Bell for giving
us an opportunity to write a bit more
about HCC. As to the relation between HCC and use of oral contraceptives, there have been at least eight casecontrol studies in countries where there is a low prevalence of hepatitis (North America, UK, Italy), all of which showed an increased risk of the development of HCC in users of oral contraceptives. Five of these studies were analysed by David Thomas‘ who found a mean risk ratio of 3.2 (range 1.5-14.5).’ Two case-control studies done in countries with a high prevalence of hepatitis have not shown this association.
THE LANCET * Vol354 -July 17,1999
The clinical picture of HCC associated with use of oral contraceptives is quite different to that in patients with hepatitis. Tumours related to use of oral contraceptives occur in the non-cirrhotic livers of women younger than 60 years. A study of HCC in six European countries showed an association of the duration of use of oral contraceptive with HCC in non-cirrhotic women younger than 65 years.’ Oestrogen exposure is also associated with other hepatic disorders such as hepatic adenomas and peliosis hepatis. Pregnancy-related mortality in the USA hovers near ten deaths per 100 000 livebirths.’ The absolute risk of HCC related to use of oral contraception is unknown, but is certainly much less than 1 per 10 000 users. Understanding, evaluating, and investigating all of the risks of contraception will make this form of therapy safer. Denying or hiding these risks will benefit no-one. Daniel F Schafer, *Michael F Sorrel/ Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 66198, USA 1 Thomas D. Exogenous steroid hormones
and hepatocellular carcinoma. In: Tabor E, Di Bisceglie A, Purcell R, eds. Etiology, pathology and treatment of hepatocellular carcinoma in North America. Texas: Portfolio, 1991: 67-89. 2 The Multicentre International Liver Tumor Study. Oral contraceptives and liver cancer. Contraception 1997; 5: 275-84. 3 Berg CJ, Atrash HK, Koonin LM, Tucker M. Pregnancy-related mortality in the United States, 1987-1990. Obstet Gynecoll996; 88: 161-67.
Sir-Daniel Schafer and Michael Sorrell’ fail to mention Budd-Chiari syndrome and acute hepatic porphyrias among the conditions associated with HCC. The evidence of HCC in patients with Budd-Chiari syndrome is high. In a study of Japanese patients with chronic Budd-Chiari syndrome, Okuda and colleagues’ found 6% incidence of HCC. Association between primary HCC and acute hepatic porphyrias have been reported in two retrospective and one case-control study.’ Andant and colleagues’ prospective cohort study’ assessed the crude annual incidence rate of primary liver cancer in 650 French carriers of the gene for acute hepatic porphyria who were followed up for 7 years. Primary liver cancer was found in seven patients, all of whom had HCC. Five patients had acute intermittent porphyria, one had variegate porphyria, and one had hereditary coproporphyria. The overall standardised rate ratio was 29. The risk
of developing HCC in carriers of the porphyria gene was particularly increased in women. *A S Kashyap, Surekha Kashyap *Department of Medicine, Armed Forces Medical College, Pune 411040, India; and Department of Hospital Administraiton, Armed Forces Medical College, Pune
1 Schafer DF, Sorrell MF. Heparocellular carcinoma. Lancet 1999; 353: 1253-57. 2 Okuda H, Yamagata H, Obata H, et al. Epidemiological and clinical studies of Budd-Chiari syndrome in Japan. In: Scheuer P, Chapman R, eds. Brighton: International Association for the Study of the Liver, Biennial Scientific Meeting, June 3-6, 1992. Brighton: IASL, 1992: OP-80 (abstr). 3 Andant D, Puy H, Faivre J, Deybach JC. Acute hepatic porphyrias and primary liver cancer. NEnglJMed 1998; 338: 1853-54.
Sir-Daniel Schafer and Michael Sorrell’s excellent review’ of HCC prompts us to report an apparent excess of patients with type 2 diabetes in an audit of patients who recently presented with HCC. A literature review identified three studies that showed an association between diabetes and increased risk of HCC. Lawson and colleagues* observed a four-fold increased risk of HCC in diabetic patients in a study designed to examine the effects of hepatic-enzyme-inducing drugs such as anticonvulsants or oral contraceptives (for which they found no evidence of excess risk). A population-based cohort of 153 852 diabetic patients also showed a four-fold risk of liver cancer in these patients, which was greater in men than in women.3 La Vecchia and co-workers’ case-control study4 reported an odds ratio risk associated with a history of diabetes of 2.3 and concluded that a history of diabetes could explain the 8% of cases of liver cancer in their population.4 It is unknown whether the fatty liver of diabetes is the hepatocellular injury which predisposes to HCC or if the presence of diabetes (which is common in cirrhosis) results in the increased susceptibility of the damaged liver to the development of HCC. We suggest that diabetes should be added to the list of risk factors associated with HCC and that persistently abnormal liver function in patients with diabetes should result in a low threshold for considering this diagnosis. Perhaps tertiary referral centres with larger series of HCC patients should review the prevalence of diabetes in their population. *Chris Deans, Peter Leslie Medical Unit, Borders General Hospital NHS Trust, Melrose, RoxburghshireTD6 9BS, UK
253
We strongly agree with The Lancet that had high-dose chemotherapy for breast cancer been available only in a clinical trial, this debate would not have ensued. ASCO supports full participation in clinical trials and hopes that the results of these five trials will spur additional large-scale studies, and that women will be encouraged to take part. John R Durant American Society of Clinical Oncology, Alexandria, VA 22314, USA
1 Editorial. Chaos surrounds high-dose chemotherapy for breast cancer. Lancer 1999; 353: 1633. 2 Marshall E. Embargos: good, bad, or “necessary evil”? Science 1998; 282: 860-68.
Hepatocellular carcinoma Sir-In their seminar on hepatocellular carcinoma (HCC), Daniel Schafer and Michael Sorrell (April 10, p 1253)’ mention that use of oral contraceptives is associated with HCC. They do not provide any citation or other evidence for this attribution, although they state that “the absolute risk of developing HCC [is] very small”. Oral contraceptives are used to prevent pregnancy, a physiological condition that does have, depending on the socioeconomic status of the population and other variables, a significant mortality. It would be important, particularly in this era of evidence-based medicine, to know what the absolute risk of developing HCC is compared with the mortality associated with pregnancy, before promulgating it as a condition associated with HCC. Bertrand M Bell Family Medicine, Jacobi Medical Center, Albert Einstein College of Medicine of Yeshiva University, Jack and Pearl Resnick Campus, Bronx, NY 10461, USA
1 Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999; 353: 1253-57.
Authors’ reply Sir-We
thank Bertrand Bell for giving
us an opportunity to write a bit more
about HCC. As to the relation between HCC and use of oral contraceptives, there have been at least eight casecontrol studies in countries where there is a low prevalence of hepatitis (North America, UK, Italy), all of which showed an increased risk of the development of HCC in users of oral contraceptives. Five of these studies were analysed by David Thomas‘ who found a mean risk ratio of 3.2 (range 1.5-14.5).’ Two case-control studies done in countries with a high prevalence of hepatitis have not shown this association.
THE LANCET * Vol354 -July 17,1999
The clinical picture of HCC associated with use of oral contraceptives is quite different to that in patients with hepatitis. Tumours related to use of oral contraceptives occur in the non-cirrhotic livers of women younger than 60 years. A study of HCC in six European countries showed an association of the duration of use of oral contraceptive with HCC in non-cirrhotic women younger than 65 years.’ Oestrogen exposure is also associated with other hepatic disorders such as hepatic adenomas and peliosis hepatis. Pregnancy-related mortality in the USA hovers near ten deaths per 100 000 livebirths.’ The absolute risk of HCC related to use of oral contraception is unknown, but is certainly much less than 1 per 10 000 users. Understanding, evaluating, and investigating all of the risks of contraception will make this form of therapy safer. Denying or hiding these risks will benefit no-one. Daniel F Schafer, *Michael F Sorrel/ Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 66198, USA 1 Thomas D. Exogenous steroid hormones
and hepatocellular carcinoma. In: Tabor E, Di Bisceglie A, Purcell R, eds. Etiology, pathology and treatment of hepatocellular carcinoma in North America. Texas: Portfolio, 1991: 67-89. 2 The Multicentre International Liver Tumor Study. Oral contraceptives and liver cancer. Contraception 1997; 5: 275-84. 3 Berg CJ, Atrash HK, Koonin LM, Tucker M. Pregnancy-related mortality in the United States, 1987-1990. Obstet Gynecoll996; 88: 161-67.
Sir-Daniel Schafer and Michael Sorrell’ fail to mention Budd-Chiari syndrome and acute hepatic porphyrias among the conditions associated with HCC. The evidence of HCC in patients with Budd-Chiari syndrome is high. In a study of Japanese patients with chronic Budd-Chiari syndrome, Okuda and colleagues’ found 6% incidence of HCC. Association between primary HCC and acute hepatic porphyrias have been reported in two retrospective and one case-control study.’ Andant and colleagues’ prospective cohort study’ assessed the crude annual incidence rate of primary liver cancer in 650 French carriers of the gene for acute hepatic porphyria who were followed up for 7 years. Primary liver cancer was found in seven patients, all of whom had HCC. Five patients had acute intermittent porphyria, one had variegate porphyria, and one had hereditary coproporphyria. The overall standardised rate ratio was 29. The risk
of developing HCC in carriers of the porphyria gene was particularly increased in women. *A S Kashyap, Surekha Kashyap *Department of Medicine, Armed Forces Medical College, Pune 411040, India; and Department of Hospital Administraiton, Armed Forces Medical College, Pune
1 Schafer DF, Sorrell MF. Heparocellular carcinoma. Lancet 1999; 353: 1253-57. 2 Okuda H, Yamagata H, Obata H, et al. Epidemiological and clinical studies of Budd-Chiari syndrome in Japan. In: Scheuer P, Chapman R, eds. Brighton: International Association for the Study of the Liver, Biennial Scientific Meeting, June 3-6, 1992. Brighton: IASL, 1992: OP-80 (abstr). 3 Andant D, Puy H, Faivre J, Deybach JC. Acute hepatic porphyrias and primary liver cancer. NEnglJMed 1998; 338: 1853-54.
Sir-Daniel Schafer and Michael Sorrell’s excellent review’ of HCC prompts us to report an apparent excess of patients with type 2 diabetes in an audit of patients who recently presented with HCC. A literature review identified three studies that showed an association between diabetes and increased risk of HCC. Lawson and colleagues* observed a four-fold increased risk of HCC in diabetic patients in a study designed to examine the effects of hepatic-enzyme-inducing drugs such as anticonvulsants or oral contraceptives (for which they found no evidence of excess risk). A population-based cohort of 153 852 diabetic patients also showed a four-fold risk of liver cancer in these patients, which was greater in men than in women.3 La Vecchia and co-workers’ case-control study4 reported an odds ratio risk associated with a history of diabetes of 2.3 and concluded that a history of diabetes could explain the 8% of cases of liver cancer in their population.4 It is unknown whether the fatty liver of diabetes is the hepatocellular injury which predisposes to HCC or if the presence of diabetes (which is common in cirrhosis) results in the increased susceptibility of the damaged liver to the development of HCC. We suggest that diabetes should be added to the list of risk factors associated with HCC and that persistently abnormal liver function in patients with diabetes should result in a low threshold for considering this diagnosis. Perhaps tertiary referral centres with larger series of HCC patients should review the prevalence of diabetes in their population. *Chris Deans, Peter Leslie Medical Unit, Borders General Hospital NHS Trust, Melrose, RoxburghshireTD6 9BS, UK
253